DESCRIPTION: It is estimated that 80 percent of significant hearing impairment in the U.S. is sensorineural or "nerve" deafness that usually originates from hair cell losses. Deficits in the sensory hair cells that convert sound and balance stimuli into neural signals have been considered irreversible, because the production of hair cells ends before birth in human ears. However, hair cells are produced postembryonically in the ears of cold-blooded animals and birds; in some, millions of hair cells are added to the ear throughout life. During past cycles of this grant it was discovered that hair cells damaged in those animals could be replaced through regenerative proliferation that was triggered by trauma. The machinery for regenerative proliferation also can operate in damaged balance organs from the ears of adult mammals, including 60-year-old humans, but that only occurs at low levels. This request for renewal of a project in its 18th year proposes to continue investigations that focus on identifying and understanding the signaling mechanisms that control the production of cells and the processes that lead to their specialization as sensory hair cells in embryonic and postembryonic ears. Those objectives will be approached in pharmacological tests, in immunohistochemistry and in situ hybridization, in expression screens that are identifying the specific molecules that function in those control mechanisms in the ear, in tests that will utilize cells derived from the ears of mice and humans and in tests of the hypothesized mechanisms in mouse mutants. The information sought is essential for the identification of targets for the development of therapeutic approaches to stimulate and control mechanisms of self-repair in the ears of mammals. The goals of this research directly pertain to possible prevention of and recovery from sensorineural hearing loss and balance dysfunctions that contribute to prevalent communication disorders and to falls by elderly individuals. They also appear likely to lead to improved understanding of the development of normal and abnormal auditory and vestibular function in human ears.